This application claims priority under 35 U.S.C. 119 from application GB 9912415.8, filed May 28, 1999.
This invention relates to novel 4-phenylpiperidines having utility in the treatment of pruritic dermatoses including allergic dermatitis and atopy in animals and humans, and processes for the preparation of and intermediates used in the preparation of such compounds.
Itching or pruritus is a common dermatological symptom which can give rise to considerable distress, in both humans and animals. Pruritus is often associated with inflammatory skin disease which can commonly be caused by hypersensitivity reactions, such as reaction to insect bites e.g. flea bites, or to environmental allergens such as house dust mite or pollen; or by bacterial and fungal infections of the skin or ectoparasite infections. Previous treatments for pruritus include the use of corticosteroids and antihistamines, however both have undesired side effects. Other therapies include the use of essential fatty acid dietary supplements which are slow to act and offer only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed but with limited success and there is a continuing need for an effective remedy.
Certain 1,3,4-trisubstituted 4-aryl-piperidine derivatives are disclosed in GB-A-1525584 as potent narcotic antagonists which also display analgesic properties. These compounds are also claimed in EP-B-0287339 as opioid antagonists which block the effect of agonists at the mu or kappa receptors having potential utility in treating a variety of disorders associated with these receptors such as eating disorders, opiate overdose, depression, smoking, alcoholism, sexual dysfunction, shock, stroke, spinal damage and head trauma; utility as an appetite suppressant for weight loss has also been suggested. Further related 1-N-substituted-4-aryl piperidines are disclosed in EP-A-0506468 and EP-A-0506478. Potential utility is suggested in preventing peripherally mediated undesired opiate effects and in relieving the symptoms of idiopathic constipation and irritable bowel syndrome.
According to the present invention we provide novel 4-phenylpiperidines which are potent and effective antipruritic agents.
Thus, the present invention provides compounds of formula I: 
wherein
R1 and R2 are each independently H or C1-4 alkyl;
R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy, C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms) and xe2x80x94N(R5a)(R5b)), C1-10 alkyl, C3-10 alkenyl or C3-10 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR5c, S(O)nR5d, CN, halo, C1-6 alkoxy carbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N(R6a)S(O)2R7, Het1, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or xe2x80x94Wxe2x80x94A1xe2x80x94N(R6b)(R6c);
n is 0, 1 or 2;
W represents a single bond, C(O) or S(O)p;
A1 represents a single bond or C1-10 alkylene;
provided that when both W and A1 represent single bonds, then the group xe2x80x94N(R6b)(R6c) is not directly attached to an unsaturated carbon atom;
p is 0, 1 or 2;
R5a to R5d each independently represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, C1-4 alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)) or Het2;
provided that R5d does not represent H when n represents 1 or 2;
R6a to R6c each independently represent H, C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl, C1-4 alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), Het3, or R6b and R6c together represent unbranched C2-6 alkylene which alkylene group is optionally interrupted by O, S and/or an N(R8) group and is optionally substituted by one or more C1-4 alkyl groups;
R7 represents C1-6 alkyl, C3-8 cycloalkyl, C1-4 alkylphenyl or aryl, which four groups are optionally substituted by or one or more substituents selected from C1-4 alkyl, C1-4 alkoxy, OH, nitro, amino or halo;
R8 represents H, C1-6 alkyl, C3-8 cycloalkyl, A2-(C3-8 cycloalkyl) or A2-aryl;
A2 represents C1-6 alkylene;
Het1, Het2 and Het3 independently represent 3- to 8-membered heterocyclic groups, which groups contain at least one heteroatom selected from oxygen, sulfur and/or nitrogen, which groups are optionally fused to a benzene ring, and which groups are optionally substituted in the heterocyclic and/or fused benzene ring part by one or more substituents selected from OH, xe2x95x90O, nitro, amino, halo, CN, aryl, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms); and
R4 represents H, C1-5 alkyl, C1-12 alkanoyl, (pyridin-3-yl)carbonyl or (pyridin-4-yl)carbonyl (which latter two groups are optionally in the pyridine N-oxide form);
or pharmaceutically, or veterinarily, acceptable derivatives thereof;
provided that, when the group OR4 is attached to the benzene ring at the meta-position relative to the piperidine ring and the piperidine is not in the N-oxide form, then:
(a) when R1 and R2 both represent C1-4 alkyl, then R3 does not represent:
C1-8 alkyl (optionally terminally substituted by C4-8 cycloalkyl);
unsubstituted C3-8 alkenyl;
unsubstituted C3-8 alkynyl;
C1-3 alkyl, terminally substituted by phenyl, phenoxy, xe2x80x94S-phenyl, xe2x80x94N(H)-phenyl or xe2x80x94N(C1-4 alkyl)-phenyl, furan-2-yl or thiophen-2-yl;
C1-4 alkyl, terminally substituted by an OH group and a further group selected from phenyl, furan-2-yl and thiophen-2-yl; or
C3-5 alkenyl, terminally substituted by phenyl, furan-2-yl or thiophen-2-yl, where the position of unsaturation is at the carbon atoms that are xcex1,xcex2 to the phenyl, furan-2-yl or thiophen-2-yl group;
all of which phenyl, phenoxy and phenylthio groups are optionally substituted by one or two substituents selected from OH, C1-3 alkyl, C1-3 alkoxy, halo, nitro, amino and CF3; and
all of which furanyl and thiophenyl groups are optionally substituted by a methyl group; and
(b) when R1 represents methyl, and:
(i) R2 represents C1-4 alkyl and R4 represents H or C1-4 alkanoyl, then R3 does not represent:
unsubstituted C3-8 alkyl;
unsubstituted C4-8 alkenyl;
C3-8 alkyl, substituted by an unsubstituted C4-8 cycloalkyl group;
C2 alkyl, terminally substituted by an unsubstituted C5-9 cycloalkanoyl, an unsubstituted C2-6 alkanoyl group or an unsubstituted thiophenyl group;
C4-9 alkyl (optionally substituted at 4- to 9-C position by C4-8 cycloalkyl) or C5-9 alkenyl, which alkyl or alkenyl groups are substituted at the 3-C position by OH, C1-6 alkoxy, oxy-C1-3-alkylphenyl or C2-5 alkanoyloxy (which latter three groups are all unsubstituted); or
C3 alkyl, terminally substituted by (1) OH, C1-6 alkoxy, oxy-C1-3-alkylphenyl or C2-5 alkanoyloxy (which latter three groups are all unsubstituted) and (2) C4-8 cycloalkyl, thiophenyl (which latter two groups are both unsubstituted); or
(ii) R2 represents H or C1-4 alkyl and R4 represents H or C1-5 alkyl, then
(I) R3 does not represent:
methyl;
C2-10 alkyl or C4-10 alkenyl, both of which are substituted at the 2-, 3- or 4-C position by xe2x80x94Wxe2x80x94A1xe2x80x94N(R6b)(R6c) and which alkyl group only is also optionally substituted at the 3- to 10-C, 4- to 10-C or 5- to 10-C position (respectively) by unsubstituted C3-8 cycloalkyl or unsubstituted phenyl; or
C1-4 alkyl, which alkyl group is terminally substituted by xe2x80x94Wxe2x80x94A1xe2x80x94N(R6b)(R6c), and is also optionally terminally substituted by unsubstituted C3-8 cycloalkyl or unsubstituted phenyl;
in which, in both cases, W is a single bond, A1 is a single bond or C1-3 alkylene, R6b or R6c is H or unsubstituted C1-10 alkyl and R6b or R6c (as appropriate) is H, C3-8 cycloalkyl, C1-10 alkyl, C3-10 alkenyl, phenyl or C1-3 alkylphenyl (which latter five groups are all unsubstituted); or
(II) R3 does not represent:
C1-10 alkyl or C3-10 alkenyl, both of which are substituted at the 1- to 5-C (as appropriate) by unsubstituted C1-6 alkoxycarbonyl or Wxe2x80x94A1xe2x80x94N(R6b)(R6c) and which alkyl or alkenyl groups are also optionally substituted at the 2- to 10-C, 3- to 10-C, 4- to 10-C or 5- to 10-C position (respectively) by unsubstituted C3-8 cycloalkyl or unsubstituted phenyl; or
C1-5 alkyl, which alkyl group is terminally substituted by an unsubstituted C1-6 alkoxycarbonyl group or xe2x80x94Wxe2x80x94A1xe2x80x94N(R6b)(R6b), and is optionally terminally substituted by unsubstituted phenyl or unsubstituted C3-8 cycloalkyl;
in which, in both cases, W is xe2x80x94C(O)xe2x80x94, A1 is a single bond, R6b or R6c is H or unsubstituted C1-3 alkyl and R6b or R6c (as appropriate) is H, C1-10 alkyl, C3-10 alkenyl, C3-8 cycloalkyl, phenyl, C1-3 alkylphenyl (which latter five groups are all unsubstituted), linear C1-4 alkyl (which latter group is terminally substituted by amino), or R6b and R6c together represent unsubstituted C3-5 alkylene;
(c) when R1 and R2 both represent methyl and are in the mutually trans-configuration and R4 represents H or C1-4 alkanoyl, then R3 does not represent:
unsubstituted C1-8 alkyl;
unsubstituted C3-8 alkenyl;
unsubstituted C3-8 alkynyl;
C1-6 alkyl, terminally substituted by an unsubstituted C3-8 cycloalkyl group;
C1-3 alkyl, terminally substituted by C3-8 cycloalkanoyl, C3-8 cycloalkoxy, C3-8 cycloalkyl, naphthyl, thiophenyl, thiophenoxy, furanyl, furanoxy, tetrahydrofuranyl, pyridinyl or pyridinyloxy (which latter eleven groups are all unsubstituted), phenyl or phenoxy (which latter two groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl and C1-4 alkoxy); or
C1-4 alkyl, terminally substituted by an OH group and by one of the following groups: phenyl (which latter group is optionally substituted by one or more substituents selected from halo, C1-4 alkyl and C1-4 alkoxy), C1-2 alkylphenyl, C3-8 cycloalkyl, thiophenyl, furanyl or pyridinyl (which latter four groups are all unsubstituted);
in all of which provisos, optionally substituted alkyl, alkenyl and alkynyl groups are not interrupted by one or more O and/or S atoms;
which compounds are referred to together hereinafter as xe2x80x9cthe compounds of the inventionxe2x80x9d.
In the definitions used herein, alkyl, alkylene, alkoxy, alkoxy carbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl parts of alkylphenyl and aryl alkoxy groups may, when there is a sufficient number of carbon atoms, be straight or branched-chain and/or optionally interrupted by one or more oxygen and/or sulfur atom(s). The term halo includes fluoro, chloro, bromo or iodo. The term xe2x80x9carylxe2x80x9d includes optionally substituted phenyl, naphthyl and the like, and xe2x80x9caryloxyxe2x80x9d includes optionally substituted phenoxy and naphthyloxy and the like. Unless otherwise specified, aryl and aryloxy groups are optionally substituted by one or more (e.g. one to three) substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy C1-4 alkoxy carbonyl and C1-5 alkanoyl (which latter four groups are optionally substituted by one or more halo atoms).
The heterocyclic rings that Het1, Het2 and Het3 represent may be fully saturated, partially unsaturated and/or wholly or partially aromatic in character. Specific rings that may be mentioned include: for Het1, dioxane, dioxolane, morpholine, piperidine, perhydroazepine, pyrazole, pyridine, triazole, tetrahydrofuran, tetrahydropyran, pyrrole, pyrrollidine or tetrazole; for Het2, tetrahydropyran.
For the avoidance of doubt, when Het (Het1, Het2 and Het3) groups are at least part-saturated, possible points of substitution include the atom (e.g. the carbon atom) at the point of attachment of the Het group to the rest of the molecule. Het groups may also be attached to the rest of the molecule via a heteroatom.
The piperidine moiety in compounds of formula I may be in N-oxidised form. Sulfur atoms that may interrupt (e.g. alkyl) substituents in compounds of formula I may be present in oxidised form (e.g. as sulfoxides or sulfones). All Het1, Het2 and Het3 groups may also be in N- or S-oxidized forms.
The term xe2x80x9cpharmaceutically, or veterinarily, acceptable derivativesxe2x80x9d includes non-toxic salts. Salts which may be mentioned include: acid addition salts, for example, salts formed with sulfuric, hydrochloric, hydrobromic, phosphoric, hydroiodic, sulfamic, organo-sulfonic, citric, carboxylic (e.g. acetic, benzoic, etc.), maleic, malic, succinic, tartaric, cinnamic, ascorbic and related acids; base addition salts; salts formed with bases, for example, the sodium, potassium and C1-4 alkyl ammonium salts.
The compounds of the invention may also be in the form of quaternary ammonium salts, e.g. at the piperdine moiety, which salts may be formed by reaction with a variety of alkylating agents, such as an alkyl halide or an ester of sulfuric, or an aromatic sulfonic acid.
The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formula I are included within the scope of the invention.
The compounds of the invention contain one or more asymmetric centres and thus they can exist as enantiomers and diastereomers. Diastereoisomers may be separated using conventional techniques e.g. by fractional crystallisation or chromatography. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques e.g. fractional crystallisation or HPLC. The desired optical isomers may be prepared by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation. Alternatively, the desired optical isomers may be prepared by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base. The invention includes the use of both the separated individual isomers as well as mixtures of isomers.
Also included within the scope of the invention are radiolabelled derivatives of compounds of formula I which are suitable for biological studies.
According to a further aspect of the invention, there is provided a compound of formula I, as hereinbefore defined, with the additional proviso that when OR4 is OH, and is attached to the benzene ring at the meta-position relative to the piperidine ring, which piperidine ring is not in N-oxidised form, then R3 represents:
optionally substituted aryl;
optionally substituted C3-10 alkenyl or C3-10 alkynyl (which two groups are both interrupted by at least one oxygen and/or sulfur atoms);
C2-10 alkyl, interrupted by at least two oxygen atoms and/or at least one sulfur atom;
C1-10 alkyl, C3-10 alkenyl or C3-10 alkynyl, which groups are all optionally interrupted by one or more oxygen and/or sulfur atoms, and are substituted and/or terminated by one or more of:
S(O)nR5d, N(R6a)S(O)2R7, Het1 (substituted by one or more substituents selected from nitro, amino and C1-5 alkanoyl (which latter group is optionally substituted by one or more halo atoms)), aryl (substituted by one or more substituents selected from nitro, amino and C1-5 haloalkanoyl) or adamantyl (which latter group is substituted by one or more of the relevant substituents identified hereinbefore); or
OR5c, in which R5c represents C7-10 alkyl, C3-10 alkenyl, C3-10 alkynyl or Het2 (which latter four groups are all optionally substituted by one or more of the relevant substituents identified hereinbefore), or R5c represents C1-10 alkyl, C1-4 alkylphenyl, C3-8 cycloalkyl or aryl (which latter four groups are all substituted by one or more of the relevant substituents identified hereinbefore);
xe2x80x94Wxe2x80x94A1xe2x80x94N(R6b)(R6c), in which R6b and/or R6c independently represent C1-4 alkylphenyl (which latter group is optionally substituted by one or more of the relevant substituents identified hereinbefore), C1-10 alkyl, C3-10 alkenyl, C3-10 alkynyl, C3-8 cycloalkyl (which latter four groups are all substituted by one or more of the relevant substituents identified hereinbefore), or aryl (substituted by one or more substituents selected from nitro, amino and C1-5 haloalkanoyl);
which compounds may also be termed xe2x80x9ccompounds of the inventionxe2x80x9d.
According to a further aspect of the invention, there is provided a compound of formula I, as hereinbefore defined, with the additional proviso that when OR4 is O-C1-4 alkyl, and is attached to the benzene ring at the meta-position relative to the piperidine ring, which piperidine ring is not in N-oxidised form, then R3 does not represent:
straight or branched-chain C1-10 alkyl (optionally substituted by one or more substituents selected from unsubstituted aryl or unsubstituted C3-8 cycloalkyl);
which compounds may also be termed xe2x80x9ccompounds of the inventionxe2x80x9d.
Preferred compounds of the invention include those wherein:
The group OR4 is attached to the benzene ring in the position meta-relative to the piperidine group;
R1 represents C1-2 alkyl;
R2 represents H or C1-2 alkyl;
R3 represents aryl (optionally substituted by one or more substituents selected from C1-2 alkyl, C1-2 alkoxy, halo, nitro and xe2x80x94N(R5a)(R5b)), C1-8 alkyl, C3-8 alkenyl or C3-8 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally interrupted by one or more oxygen atoms and/or are substituted and/or terminated by one or more substituents selected from OR5c, S(O)nR5d, CN, halo, C1-4 alkoxy carbonyl, C4-6 cycloalkyl, C5-7 cycloalkanoyl, Het1, aryl (which latter group is optionally substituted by one or more substituents selected from OH, C1-2 alkyl, C1-2 alkoxy or halo), or xe2x80x94Wxe2x80x94A1xe2x80x94N(R6b)(R6c);
W represents a single bond or C(O);
A1 represents a single bond or C1-3 alkylene;
R5a to R5d each independently represent H, C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, C4-8 cycloalkyl, C1-2 alkylphenyl, aryl or Het2;
R6b and R6c independently represent H, C1-2 alkyl, Het3, or R6b and R6c together represent unbranched C2-6 alkylene which alkylene group is optionally interrupted by O or S and is optionally substituted by one or more C1-2 alkyl groups;
Het1, Het2 and Het3 independently represent 5- to 7-membered heterocyclic groups, which groups contain at least one heteroatom selected from oxygen, sulfur and/or nitrogen, which groups are optionally fused to a benzene ring, and which groups are optionally substituted in the heterocyclic and/or fused benzene ring part by one or more substituents selected from OH, xe2x95x90O and C1-2 alkyl (which latter group is optionally substituted by one or more halo atoms);
R4 represents H or C1-5 alkanoyl.
More preferred compounds of the invention include those wherein:
R1 represents methyl;
R2 represents H or methyl;
R3 represents phenyl (optionally substituted by one or more substituents selected from methyl, methoxy and xe2x80x94N(CH3)2), linear C1-7 alkyl or linear C1-7 alkenyl, which alkyl or alkenyl groups are optionally interrupted by one or more oxygen atoms and/or are optionally substituted and/or terminated by one or more substituents selected from OR5c, S(O)nR5d, C1-2 alkoxy carbonyl, C4-6 cycloalkyl, Het1 or xe2x80x94C(O)N(R6b)(R6c);
R5c and R5d each independently represent H, C1-3 alkyl, C3-4 alkenyl, C5-7 cycloalkyl, phenyl, naphthyl or Het2;
R6b and R6c together represent unbranched C4-6 alkylene which alkylene group is optionally interrupted by O and is optionally substituted by one or more C1-2 alkyl groups;
Het1 and Het2 independently represent 5- to 7-membered heterocyclic groups, which groups contain at least one heteroatom selected from oxygen, sulfur and/or nitrogen, and which groups are optionally substituted by one or more C1-2 alkyl groups.
Particularly preferred compounds of the invention include those wherein:
R1 and R2 represent methyl groups in the mutually trans configuration;
R4 represents H.
Preferred compounds of the invention include the compounds of the Examples described hereinafter.
Thus, according to a further aspect of the invention, there is provided a compound of formula I which, irrespective of any of the foregoing definitions and/or provisos, is:
(xc2x1)-3-{1-[2-(cyclohexyloxy)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[2-(1,3-dioxan-2-yl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(3-hydroxypropyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-{1-[3-(allyloxy)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(2-ethoxyethyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-[1-(3-tetrahydro-3-furanylpropyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-{1-[2-(2-methoxyethoxy)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(2-methoxyethyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-{1-[2-(vinyloxy)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-(1-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}-trans-3,4-dimethylpiperidinyl)phenol;
(xc2x1)-3-{1-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(3-tetrahydro-2H-pyran-2-ylpropyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-{1-[3-(1,3-dioxan-2-yl)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(3,3-dimethoxypropyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-{1-[2-(2-hydroxyethoxy)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[2-(1,3-dioxolan-2-yl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[4-(1,3-dioxolan-2-yl)butyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[2-(2,5,5-trimethyl-1,3-dioxan-2-yl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(5-hydroxypentyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-[1-(3-tetrahydro-2H-pyran-4-ylpropyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-{1-[2-(2-naphthyloxy)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(2-isopropoxyethyl)-trans-3,4-dimethylpiperidinyl]phenol; 3-[1-(2-propoxyethyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-{1-[2-(cyclopentyloxy)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(3-tetrahydro-2-furanylpropyl)-trans-3,4-dimethylpiperidinyl]phenol;
(xc2x1)-3-{1-[2-(cyclohexylsulfanyl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[2-(ethylsulfanyl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[2-(ethylsulfinyl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[2-(ethylsulfonyl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[3-(1H-1,2,3,4-tetrazol-1-yl)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[3-(1H-pyrazol-1-yl)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[3-(4-pyridinyl)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[3-(1H-1,2,4-triazol-1-yl)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-{1-[3-(1H-pyrrol-1-yl)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinyl]-1-(4-morpholinyl)-1-propanone;
3-{1-[3-(4-morpholinyl)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
3-{1-[2-(1-azepanyl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
3-{1-[2-(4-morpholinyl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
3-{1-[2-(1-piperidinyl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
3-{1-[2-(1-pyrrolidinyl)ethyl]-trans-3,4-dimethylpiperidinyl}phenol;
3-{1-[3-(1-piperidinyl)propyl]-trans-3,4-dimethylpiperidinyl}phenol;
(xc2x1)-3-[1-(3-methoxyphenyl)-trans-3,4-dimethylpiperidinyl]phenol; or
(xc2x1)-3-{1-[4-(dimethylamino)phenyl]-trans-3,4-dimethylpiperidinyl}phenol; or
(xc2x1)-methyl 3-[trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidinyl]propionate,
which compounds may also be termed xe2x80x9ccompounds of the inventionxe2x80x9d.
According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated below.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention.
1. Compounds of formula I wherein R3 represents C1 alkyl optionally substituted by C3-8 cycloalkyl, Het1, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or R3 represents C2-10 alkyl, C3-10 alkenyl or C3-10 alkynyl (which three groups are all optionally substituted by one or more of the relevant substituents identified hereinbefore in respect of R3), which alkyl, alkenyl or alkynyl groups are attached to the piperidine nitrogen atom via a CH2 group, wherein Het1 is as hereinbefore defined, may be prepared by reduction of a corresponding compound of formula II, 
wherein R31 represents H, C3-8 cycloalkyl, Het1, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), C1-9 alkyl, C2-9 alkenyl or C2-9 alkynyl, which alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR5c, S(O)n5d, CN, halo, C1-6 alkoxy carbonyl, C2-6 alkanoyl, C2-6 alkanoyloxy, C3-8 cycloalkyl, C4-9 cycloalkanoyl, N(R6a)S(O)2R7, Het1, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-4 alkyl, C1-4 alkoxy and C1-5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or xe2x80x94Wxe2x80x94A1xe2x80x94N(R6b)(R6c), and R1, R2, R4, R5c, R5d, R6a to R6c, R7, Het1, n, W and A1 are as hereinbefore defined, using a suitable reducing agent (e.g. lithium aluminium hydride or a borane derivative), for example as described hereinbefore.
Compounds of formula II may be prepared by reaction of a corresponding compound of formula III, 
wherein R1, R2 and R4 are as hereinbefore defined with a compound of formula IV,
xe2x80x83R31CO2Hxe2x80x83xe2x80x83IV
or a suitable (e.g. carboxylic acid) derivative thereof (e.g. an acid halide or anhydride), wherein R31 is as hereinbefore defined, using coupling conditions known to those skilled in the art.
Compounds of formula III may be prepared from appropriate precursors by analogy with other methods disclosed herein that describe the production of compounds of formula I.
2.Compounds of formula I in which R4 represents C1-12 alkanoyl, (pyridin-3-yl)carbonyl or (pyridin-4-yl)carbonyl (which latter two groups are optionally in the pyridine N-oxide form) may be prepared by reaction of a corresponding compound of formula I in which R4 represents H with a compound of formula V,
R41xe2x80x94CO2Hxe2x80x83xe2x80x83V
or a suitable (e.g. carboxylic acid) derivative thereof (e.g. an acid halide or anhydride), wherein R41 represents C1-11 alkyl, pyridin-3-yl or pyridin-4-yl (which latter two groups are optionally in the pyridine N-oxide form), using coupling conditions known to those skilled in the art.
3. Compounds of formula I may also be prepared by reaction of a corresponding compound of formula III, as hereinbefore defined, with a compound of formula VI,
R3xe2x80x94L1xe2x80x83xe2x80x83VI
wherein L1 represents a leaving group such as halo, alkanesulfonate, perfluoroalkanesulfonate or arenesulfonate) and R3 is as hereinbefore defined, under conditions that are well known to those skilled in the art, which include, for example, alkylation at between room temperature and reflux temperature in the presence of a reaction-inert organic solvent (e.g. N,N-dimethylformamide) and a suitable base (e.g. NaHCO3), and arylation at between room temperature and reflux temperature in the presence of a suitable catalyst system (e.g. tris(dibenzylideneacetone)palladium(0) combined with tri-o-tolylphosphine), an appropriate strong base (e.g. sodium tert-butoxide) and a reaction-inert solvent (e.g. toluene).
4. Compounds of formula I wherein R3 represents C1 alkyl, which, in place of being optionally substituted by the substituents as defined hereinbefore, is instead optionally substituted by R31, wherein R31 is as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula III, as hereinbefore defined, with a compound of formula VII,
R31CHOxe2x80x83xe2x80x83VII
wherein R31 is as hereinbefore defined, for example in the presence of a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride) and an appropriate solvent (e.g. methanol).
5. Compounds of formula I wherein R3 is a C1-10 alkyl, C4-10 alkenyl or C4-10 alkynyl group that is fully saturated from 1- to 3-C (relative to the piperidine N-atom), and which R3 group is substituted at 2-C (relative to the piperidine N-atom) by S(O)R5d, S(O)2R5d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, xe2x80x94C(O)xe2x80x94A1xe2x80x94N(R6b)(R6c), xe2x80x94S(O)xe2x80x94A1xe2x80x94N(R6b)(R6c), or xe2x80x94S(O)2xe2x80x94A1xe2x80x94N(R6b)(R6c), wherein R5d, R6b, R6c and A1 are as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula III, as hereinbefore defined, with a compound of formula VIII,
R3axe2x80x94Zxe2x80x83xe2x80x83VIII
wherein R3a represents R3 as hereinbefore defined except that it does not represent aryl, and that the R3a chain contains an additional carbon-carbon double bond xcex1,xcex2 to the Z-substituent, and Z represents S(O)R5d, S(O)2R5d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, xe2x80x94C(O)xe2x80x94A1xe2x80x94N(R6b)(R6c), xe2x80x94S(O)xe2x80x94A1xe2x80x94N(R6b)(R6c) or xe2x80x94S(O)2xe2x80x94A1xe2x80x94N(R6b)(R6c), wherein R5d, R6b, R6c and A1 are as hereinbefore defined, for example at between room and reflux temperature in the presence of a reaction-inert solvent (e.g. THF).
Compounds of formulae IV to IX, and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions (see, for example, xe2x80x9cComprehensive Organic Transformationsxe2x80x94A Guide to Functional Group Preparationsxe2x80x9d, R. C. Larrock, VCH (1989), or xe2x80x9cAdvanced Organic Chemistryxe2x80x94Reactions, Mechanism and Structurexe2x80x9d, 4th edition, J. March, Wiley-Interscience (1992)). For example, compounds of formula I in which R4 represents H may be made according to or by analogy with the procedures disclosed in the publications mentioned above relating to 4-arylpiperidine-based compounds.
Substituents on alkyl, heterocyclic and aryl groups in the above-mentioned compounds may also be introduced, removed and interconverted, using techniques which are well known to those skilled in the art. For example, nitro may be reduced to amino, OH may be alkylated to give alkoxy, alkoxy may be hydrolysed to OH, alkenes may be hydrogenated to alkanes, halo may be hydrogenated to H, etc.
The skilled person will also appreciate that other various standard substituent or functional group interconversions and transformations within certain compounds of formula I will provide other compounds of formula I.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the course of carrying out the processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include oxo, OH, amino and carboxylic acid. Suitable protective groups for oxo include acetals, ketals (e.g. ethylene ketals) and dithianes. Suitable protective groups for OH include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protective groups for amino include tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protective groups for carboxylic acid include C1-6 alkyl or benzyl esters. Suitable protective groups for terminal alkynes include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl).
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protective groups may be removed in accordance with techniques which are well known to those skilled in the art.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J W F McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991).
Persons skilled in the art will also appreciate that, in order to obtain compounds of formula I in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis. The procedures may be adapted as appropriate to the reactants, reagents and other reaction parameters in a manner that will be evident to the skilled person by reference to standard textbooks and to the examples provided hereinafter.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of formula I may act as prodrugs of other compounds of formula I.
It will be further appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as xe2x80x9cpro-moietiesxe2x80x9d, for example as described in xe2x80x98Design of Prodrugsxe2x80x99 by H. Bundgaard, Elsevier, 1985 (the disclosure in which document is hereby incorporated by reference), may be placed on appropriate functionalities, when such functionalities are present within compounds of formula I.
All protected derivatives, and prodrugs, of compounds of formula I are included within the scope of the invention.
Pharmaceutically acceptable acid addition salts of the compounds of formula I which contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt may then be isolated either by filtration of by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula I with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The above procedures may be adapted as appropriate to the particular reactants and groups involved and other variants will be evident to the skilled chemist by reference to standard textbooks and to the examples provided hereafter to enable all of the compounds of formula I to be prepared.
The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals including humans. They are therefore indicated as pharmaceuticals and, in particular, for use as animal medicaments.
According to a further aspect of the invention there is provided the compounds of the invention (optionally a compound of formula I as defined herein but without the provisos) for use as medicaments, such as pharmaceuticals and animal medicaments.
By the term xe2x80x9ctreatmentxe2x80x9d, we include both therapeutic (curative) or prophylactic treatment.
In particular, the compounds of the invention have been found to be useful in the treatment of pruritus, and conditions characterised by pruritus as a symptom.
Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention (optionally a compound of formula I as defined herein but without the provisos) in the manufacture of a medicament for the treatment of pruritus or a medical condition characterised by pruritus as a symptom.
The compounds of the invention are thus expected to be useful for the curative or prophylactic treatment of pruritic dermatoses including allergic dermatitis and atopy in animals and humans. Other diseases and conditions which may be mentioned include contact dermatitis, psoriasis, eczema and insect bites.
Thus, the invention provides a method of treating or preventing pruritus or a medical condition characterised by pruritus as a symptom in an animal (e.g. a mammal), which comprises administering a therapeutically effective amount of a compound of the invention (optionally a compound of formula I as defined herein but without the provisos) to an animal in need of such treatment.
The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses (see below).
While it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical, or veterinary, formulation comprising a pharmaceutically, or veterinarily, acceptable carrier, diluent or excipient and a compound of the invention. The carrier, diluent or excipient may be selected with due regard to the intended route of administration and standard pharmaceutical, and/or veterinary, practice. Pharmaceutical compositions comprising the compounds of the invention may contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient.
The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.
The formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more usually about 5 to about 300 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discreet units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
In any event, the veterinary practitioner, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
For veterinary use, the compounds of the invention are of particular value for treating pruritus in domestic animals such as cats and dogs and in horses.
As an alternative for treating animals, the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablet, capsule and ointment preparations which are formulated in accordance with standard pharmaceutical practice.
Compounds of the invention may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of illustration and should not be construed as limiting) include antiparasitics, e.g. fipronil, lufenuron, imidacloprid, avermectins (e.g. abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, e.g. chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, e.g. fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, e.g. enroflaxacin, marbofloxacin, ampicillin, amoxycillin; anti-inflammatories e.g. prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, e.g. gamma-linoleic acid; and emollients. Therefore, the invention further provides a product containing a compound of the invention and a compound from the above list as a combined preparation for simultaneous, separate or sequential use in the treatment of pruritus.
The skilled person will also appreciate that compounds of the invention may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
Thus, according to a further aspect of the invention there is provided a pharmaceutical, or veterinary, formulation including a compound of the invention (optionally a compound of formula I as defined herein but without the provisos) in admixture with a pharmaceutically, or veterinarily, acceptable adjuvant, diluent or carrier.
Compounds of the invention may also have the advantage that, in the treatment of human and/or animal patients, they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
The biological activity of the compounds of the present invention was determined by the following test method.
The compounds of the invention are evaluated for their activity as antipruritic agents by measuring their ability to inhibit the hind leg scratching behaviour induced in rats by the administration of a known pruritogenic agent. These studies are based on the procedure described by Berendsen and Broekkamp in the European Journal of Pharmacology, 1991, 194, 201. The test is performed as follows:
Male Wistar rats (approximately 150 g body weight) are challenged with a pruritogen by subcutaneous injection of 5-methoxytryptamine hydrochloride (4 mg/3 mL/kg) dissolved in physiological saline into the scruff of the neck. At this dose a constant and quantifiable hindleg scratching response lasting up to 90 minutes is obtained.
The test compound is administered to the test animals by subcutaneous injection in an aqueous micelle formulation. The test compound is prepared in the following manner. The compound is dissolved in a vehicle (composition v/v%: glycerol formal, 24; tween 80, 17; benzyl alcohol, 1.5 and purified water to 100) then seven parts purified water is added to three parts of the above vehicle to give the aqueous micelle formulation. The compounds can be administered pre- or post-challenge or may be administered at the same time as the pruritogenic challenge.
After the pruritogen challenge has been administered, hindleg scratching is scored for each animal by recording the presence or absence of scratching during each 30 second interval as 1 or 0 scored respectively. The score for each animal is totalled after 25 minutes (maximum score 50). The efficacy of compounds is assessed by their ability to significantly reduce the score in treated groups compared to the control group.
The invention is illustrated by the following Preparations and Examples in which the following abbreviations may be used:
APCI =atmospheric pressure chemical ionisation
br (in relation to NMR)=broad
DCM=dichloromethane
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
d (in relation to time)=day
d (in relation to NMR)=doublet
dd (in relation to NMR)=doublet of doublets
EtOAc=ethyl acetate
EtOH=ethanol
h=hour(s)
m (in relation to NMR)=multiplet
MeOH=methanol
min=minute
q (in relation to NMR)=quartet
rt=room temperature
s (in relation to NMR)=singlet
t (in relation to NMR)=triplet
THF=tetrahydrofuran
TSI=thermospray ionisation
When column chromatography is referred to this usually refers to a glass column packed with silica gel (40-63 xcexcm). Pressure of about 165 kPa is generally applied and the ratio of crude product : silica gel required for purification is typically 50:1. Alternatively, an Isolute(trademark) SPE (solid phase extraction) column or Waters Sep-Pak(trademark) cartridge packed with silica gel may be used under atmospheric pressure. The ratio of crude product to silica gel required for purification is typically 100:1.
Hydrochloride salts of the compounds of the examples may be made by methods known to those skilled in the art of synthetic chemistry. For example, ethereal hydrochloric acid (1.0 M, 1.2 equivalent) may be added to a solution of free base in dichloromethane (1 g:100 mL), the excess solvent decanted off and the remaining precipitate washed three times with ether and dried in vacuo.
A common starting material, (xc2x1)-3-(trans-3,4-dimethylpiperidinyl)phenol, can be prepared using the procedures described in: a) Zimmerman et al, J. Org. Chem., 1991, 56, 1660; b) Werner et al, J. Org. Chem., 1996, 61, 587-597. All starting materials were obtained from commercial sources unless stated otherwise.
Nuclear magnetic resonance (NMR) spectral data were obtained using a Brucker AC3000, AM300 or AM400 spectrometer, the observed chemical shifts (xcex4) being consistent with the proposed structures. 1H-NMR data are measured in solution in CDCl3 unless otherwise specified. Mass spectral (MS) data were obtained on a Finnigan Mat. TSQ 7000 or a Fisons Instruments Trio 1000 spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest mass. HPLC means high performance liquid chromatography. Room temperature means 20 to 25xc2x0 C.